Substituted sulfonyl bornane-carboxamides and nonbornane carboxamides

ABSTRACT

Bicyclic carboxamide derivatives, prepared, inter alia, by reacting, for example, a camphor-3-carboxylic acid or noncamphor3-carboxylic acid derivative with a sulfonic acid amide, are described. The bicyclic carboxamide derivatives are useful as hypoglycemic agents.

United States Patent [191 Bretschneider et al.

[73] Assignee: Hoffman-La Roche Inc., Nutley,

221 Filed: Oct.l0,1972

211 Appl. No.: 296,481

Related US. Application Data [62] Division of Ser. No. 8,390, Feb. 3, I970, Pat. No.

[52] US. Cl. 260/293.56, 260/32639 [5]] Int. Cl C07d 29/34 [58] Field of Search 260/293.56, 326.3

[451 June 28, 1974 [56] ReferencesCited UNITED STATES PATENTS 3,654,357 4/1972 Bretschneider et al. 260/552 R FOREIGN PATENTS OR APPLICATIONS 902,88l 8/1962 Great Britain Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm'Samuel L. Welt; Bernard S. Leon; William G. Isgro ABSTRACT Bicyclic carboxamide derivatives, prepared, inter alia,

by reacting, for example, a camphor-3-carboxylic acid" or noncamphor-3-carboxylic acid derivative with a sulfonic acid amide, are described. The bicyclic carboxamide derivatives are useful as hypoglycemic agents.

5 Claims, No Drawings l SUBSTITUTED SULFONYL BORNANIfl-CARBOXAMIDES AND NONBORNANE CARBOXAMIDES CROSS-REFERENCE TO RELATED APPLICATIONS pounds of the formula /l\ a R R R OONHSOzR" wherein the residues R are identicaland are hydrogen or methyl, R is hydrogen, R is hydroxy, or R and R taken together, are the oxygen atom of a keto group (which can also be ketalized), and R is phenyl; phenyl substituted by halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, acylamino, acylamino-lower alkyl, cyano, carbamoyl or diacylimido; cycloalkyl; or a 5- or 6-membered N- linked nitrogen-containing heterocyclic residue, and salts thereof with ,pharmaceutically acceptable bases. The compounds of formula I are useful as hypoglycemic agents.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to bornanecarboxamides of the formula Compounds of this invention corresponding to formula I are exemplified by the following: lR)-2-Oxo-N-(piperidinosulfonyl )-3-endobornanecar-boxamide; rac. 2-Oxo-N-(p-tolylsulfonyl)-3-bornanecarboxamide (mixture of endo and exo isomer); v IR )-2-Oxo-N-( p-tolylsulfonyl )-3-endobornanecarboxamide; isomeric 'tolylsulfonyl)-3-endobornanecarboxamide and l- R )-2 -endohydroxy-N-( p-tolylsulfonyl )-3-exobornanecarboxamide;

mixture of lR)-2-exo-hydroxy-N-(p-i 2 1 Isomericmixture of (lR)- 2-endohydroxy-N-(ptolylsulfonyl)-3-endobomanecarboxamide and l- R )-2-exohydroxy-N-(p-tolylsulfonyl )-3-exoborna'necarboxamide; V IR)-N-I(P-Chlorophenyl )-sulfonyl ]-2-oxo-3- endobomanecarboxamide: lR)-N- [p-(methyIthio)-phenyl]-sulfonyl} -2-oxo-3-endobornanecarboxamide sodium; 1R)-N- [p-(ethylthio)-phenyl ]-sulfonyl -2-oxo-3-endobornanecarboxamide sodium; lR)-N- {[p-(Z-acetamidoethyl)-phenyl]-sulfonyl -2-oxo-3-endoborn anecarboxamide sodium; 1R)-N-(N-acetylsulfanilyl)-2-oxo-3-endobornanecarboxamide sodium; lR)-2-oxo-N-sulfanilyl-3-endobornanecarboxamide sodium; lR)-N-[(p-carbamoylphenyl)-sulfonyl]-2-oxo-3- bornanecarboxamide sodium;

(lR)-N-[ {p-[2-(5-chloro-o-anisamido)-ethyll-phenyl} -sulfonyl]-2-oxo-3-endobornanecarboxamide; and 1R) N-[(p-cyanophenyl)-sulfonyl]-2-oxo3- endobornanecarboxamide. As used herein, the term alkyl denotes preferably straight or branched chain lower alkyl groups having l6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, phenyl, hexyl, and their isomers. The term "alkoxy" preferably denotes a lower alkyl ether group in which the lower alkyl group is as described above, for example, methoxy, ethoxy, propoxy, pentoxy, and the like. The term alkylene denotes a hydrocarbon group of 1-6 carbon atoms, for example,

methylene, ethylene, propylene, butylene, pentylene, and the like. The term halogen"denotes all the halogens, i.e., bromine, chlorine, fluorine and iodine; preferably, chlorine and bromine.

A halophenyl represented by R is preferably chlorophenyl. The term acyl denotes an aliphatic or aromatic acyl residue, for example, an alkanoyl group derived from an aliphatic carboxylic acid of l7 carbon atoms,' such as formyl, acetyl, propionyl, and the like; and an aroyl" group derived from an aromatic carboxylic acid, such as benzoyland the like.

Exemplary of acylaminophenyl are acetaminophenyl, benzoylaminophenyl and the like. Exemplary of diacylimidophenyl are phthalimidophenyl and the like. An 'acylaminoalkylphenyl residue is, for example, benzylaminoethylphenyl, which is substituted in the benzamide residue by lower alkoxy or halogen. Exemplary of 5,- or 6-membered nitrogen-containing heterocyclic rings are piperidinyl and pyrrolidinyl. The term cycloalkyl" preferably denotes a cyclo-lower alkyl group of 3-6 carbon atoms, for example, cyclopentyl, cyclohexyl and the like.

As ketals there come into consideration, for example, dialkyl ketals such as the dimethyl or diethyl ketals; or alkylene ketals such as the ethylene ketal.

.The compounds of formula I can be prepared in accordance with the invention, by the following process variants:

(A) By reacting a reactive camphor-3-carboxylic acid or norcamphor-3-carboxylic' acidderivative, in which the ring-located keto group can be ketalized, with a sulfonic acid amide of the formula 3 wherein R is R as described above wherein amino is protected, or an alkali salt thereof; or

(B) Y By reacting camphor-3-carboxylic acid, norcamphor-3-carboxy1ic acid or a camphor or norcamphor alkali salt, in which compounds the ringlocated keto group can be ke'talized, with a sulfonyl isocyanate of the formula R SO NCO 111 and, if desired, removing the protecting groups from a protected amino group, saponifying a cyano group to carbamoyl,

cleaving a ketal group, reducing a ring-located keto group to hydroxy,and/or' converting the reaction product into a salt with a pharmaceutically acceptable base. The starting materials utilized in the process of the invention are known compounds or can beprepared according to known procedures.

The reaction of a compound of formula II or 111 with one of the named camphor or norcamphor derivatives is conveniently carried out in a suitable organic solvent,

conveniently with heating. Suitable solvents comprise, for example. hydrocarbons such as benzene; halogenated hydrocarbons such as chloroform; dimethylformamide, and the like.

As protecting groups for the amino group in process variant (A) there can be utilized, for example, acyl resi dues such as the acetyl, removal of which can be effected in a known manner, for example, by mild hydrolysis. The saponification of a cyano group can be ef fected by treatment with alkali such as, for example, an

uratively from DL- or D-camphor, respectively, from borneol or isoborneol.

The compounds of formula I form salts with pharmaceutically acceptable bases and such salts are also within the scope of the invention. Thus, the compounds of formula I form salts with pharmaceutically acceptable bases, which preferably include alkali metal bases, such as sodium hydroxide, potassium hydroxide and the like, and organic bases, such as trialkylamines, e.g. triethylamine.

The compounds of formula 1 are useful as hypoglycemic agents. Their hypoglycemic activity can be demonstrated in warm-blooded animals as described hereinafter. Female dogs, which after 1-day standard diet have been fasted for 16 hours, are utilized in groups of three for each test compound and dosage level. The test compounds are administered per es in gelatin capsules. Blood samples are taken prior to the medication and at prescribed intervals thereafter. After heparinization, the plasma is separated and its glucose content is determined according to the glucose oxidase method (Anal, Biochem. 3, 131, [1962 in the Technicon Autoanalyzer. Four percent ox albumin solution with a known amount of glucose is used as the standard. The results obtained are statistically evaluated and calculated as percent deviation from the blank value. Positive values signify increases, negative values decreases of the plasma glucose concentration.

Utilizing the procedure set forth above, when p. mol. of a compound of formula I of the invention is administered, the results set forth in Table 1 are obtained:

TABLE 1 Hypoglycemic Compound Activity Time endobornanecarboxamide 257r after 24 hrs. (IR N-[{p-[2-(5chloro-o-anisamido)- 3endob0rnanecarboxamide 27'/ after 4 hrs. (1R)- N-{Ip-(nicthylthio)phenyllhornanecarboxamide l67r after 4 hrs.

alkali metal hydroxide.

The cleavage of a ketal group can be carried out with acidic agents, for example, mineral acids such as hydrochloric acid and the like, preferably in the presence of an organic solvent such as acetone. A ring-located keto group which may be present in the obtained reaction products can subsequently be reduced to the hydroxy group in a known manner, for example, by treatment with a complex metal hydride such as sodium borohydride, or by catalytic hydrogenation. Cis-trans isomers obtained in the reduction can then, if desired, be separatedaccording to known methods, for example, by crystallization or by chromatography.

The compounds of formula I obtained in accordance with the invention can exist in different configurations depending on the stereochemistry of the bicyclic starting materials, for example, they can exist as the racemate or the optically active antipodes. The optically active antipodes can be separated according to known procedures. Preferred compounds of formula I are those in which R is lower alkylphenyl, lower alkylthiophenyl or acylamino lower alkylphenyl and, of these, especially preferred are those which are derived config- EXAMPLE 1 Preparation of 1R)-2-oxo-n-(piperidinosulfonyl)-3-endobornanecarf boxamide 1.6 g. of sulfamylpiperidine and 1.1 g. of triethylamine are dissolved in 10 ml. of dimethylformamide, and a solution containing 2.1 g. of D-camphorcarboxylic acid chloride in 5 ml. of benzene is added dropwise thereto over a period of 15 minutes. After stirring overnight, the solvent is removed by evaporation on the rotary evaporator. The resulting viscous oil crystallizes when added to 50 ml. of water, whereby there are obv D-camphor-3-carboxylic 5 tained 2 g. of (lR)-2-oxo-N-(piperidinosulfonyl )-3- endobornanecarboxamide having a melting point of 153 (from ethanol), [01],, 792 (in chloroform).

EXAMPLE 2 Preparation of rac. 2-oxo-N-(p-tolylsulfonyl)-3-bomanecarboxamide 20 g. of D,L-camphor-3-carboxylic acid are heated to 100C. with 40 ml. of tosyl isocyanate over a period of 30 minutes and maintained at this temperature for about 1 hour until the end of the evolution of C The reaction mixture is partitioned between 500 ml. of

ether and 1 liter of 0.5-N sodium hydroxide. The aqueous alkaline extract is slowly brought to pH by addition of dilute hydrochloric acid with stirring and cooling. The oily product obtained is filtered and washed with cold water. It crystallizes after being taken up in a little ether. The product is purified by first being dissolved in ethyl acetate andthen being precipitated with petroleum ether. The product is subsequently recrystallized from dilute'alcohol, whereby there are obtained g. of rac. 2'oxo-N-(p-tolylsulfonyl)-3-bornanecarboxamide as a mixture of the endo and exo isomer having a melting point of 78-80.

EXAMPLE 3 Preparation of lR)-2-oxo-N-(p-tolylsulfonyl)--3-endobornanecarboxamide lnan analogous manner to Example 2, starting from D-camphor-B-carboxylic acid there is obtained lR)-2- oxo-N-( p-tolylsulfonyl )-3-endobornanecarboxamide having a melting point of l39'l49 (dec.) (from ethanol/water); [01] 94.7 (in chloroform).

EXAMPLE 4 and,- after the addition of 100 ml. of 1N sodium hydroxide, dissolved by gentle heating. 8 g. of-NaBH are then I introduced all at once and the reaction mixture heated on awater-bath for 2 hours. After the addition of an ad I ditional 4 g. of NaBH the mixture is heated on a boiling water-bath for another 2 hours. The acidic ingredients are precipitated from the cooled reaction mixture with dilute acetic acid as a flocculent precipitate which, after washing with water, is again dissolved in 300 ml. of 1N NaOH and heated on a boiling water-bath for 4 hours. The precipitate obtained by acidification with acetic acid is crystallized from dilute alcohol, whereby there are obtained 12 g. of an isomeric mixture of (IR- )-2-exo-hydroxy-N-(p-tolylsulfonyl)-3-endobornanecarboxamide and lR)-2-endo-hydroxy-N-(ptolylsulfonyl)-3-exobornanecarboxamide which melts at 170 (from ether/petroleum ether).

EXAMPLE 6 is extracted with ethyl acetate, and the residue of the neutral-washed ethyl acetate extract is fractionally crystallized from ether-petroleum ether, whereby there are obtained 1.3 g. of an isomeric mixture of lR)-2- endo-hydroxy-N-(p-tolylsulfonyl)-3-endobornanecarboxamide and lR)-2-exo-hydroxy-N-( ptolylsulfonyl)-3-exobornan carboxamide, having a melting point of 164 (from ethyl acetate/petroleum ether).

EXAMPLE 7 Preparation of lR)-2-oxo-N-( p-tolylsulfonyl )-3-endobornanecarboxamide Asolution containing 15 g. of camphor and 4 g. of NaNH (sodium amide) in ml. of benzene is added dropwise with stirring and external ice-cooling to a solution containing 3 g. of tosyl isocycnate in 50 ml. of benzene. The reaction mixture is partitioned between ice-water and ether. Thereafter, the aqueous phaseis washed with ether and acidified. Afterdecantation of the solvent, the tarry precipitated acidic ingredients are taken up methyl acetate and evaporated. The residue of the ethyl acetate phase is crystallized from ethyl acetate/petroleum ether, whereby there are obtained 0.3 g. of (lR)-2-oxo-N-(p-tolylsulfonyl)-3-endob0rnanecarboxamide which is identical with the compound obtained in accordance with Example 3.

EXAMPLE 8 Preparation of v lR)-N-[(p-chlorophenyl)-sulfonyl]-2-oxo-3-endobornanecarboxamide EXAMPLE 9 Preparation of (1R)-N- I [p-(methylthio )phenyl ]-sulfonyl} -2-oxo- 3-endobomanecarboxamide sodium In an analogous manner to Example 2, from D-camphor-3-carboxylic acid and p-methylthiobenzenesulfoisocyanate there is obtained (lR)-N- {[p-( methylthio )phenyl -sulfonyl} -2-oxo-3- endobornanecarboxamide. On addition of D-camphor-3-carboxylic 7 aqueous sodium hydroxide solution to the alcoholic solution of the compound there is obtained the sodium salt having a melting point of l90l92 (from ethanol).

EXAMPLE l Preparation of lR)-N-{[p-(ethylthio)phenyl]-sulfonyl} -2-oxo-3-endobornanecarboxamide sodium In an analogous manner to Example 1, from D-camphor-3-carboxylic acid chloride and p-ethylthiobenzenesulfonamide, there is obtained (lR)-N- {[p-(ethylthio)-phenyl]-sulfonyl} -2-oxo-3 -endobornanecarboxamide. The sodium salt melts at l52l54 (from ethanol/ether).

EXAMPLE 1 1 Preparation of lR)-N- {[p-(2-acetamidoethyl)phenyl]-sulfonyl} -2-oxo-3-endobornanecarboxamide sodium In an analogous manner to Example 1, from acid chloride and p- (acetylaminoethyl)-benzene-sulfonamide there is obtained (lR)-N- {{p-( 2-acetamidoethyl )-phenyl]-sulfonyl} -2-oxo-3- endobornanecarboxamide. The sodium salt melts at l78-l80 (from ethanol).

EXAMPLE 12 Preparation of lR)-N-(N-acetylsulfanily )-2-oxo-3-endobornanecarboxami'de sodium ln an analogous manner to Example 1, from D-camphor-3-carboxylic acid chloride and pacetylaminobenzenesulfonamide there is obtained 1R- )-N-(N-acetylsulfanilyl)-2-oxo-3-endobornanecarboxamide. The sodium salt melts at 240 (from ethanol).

EXAMPLE 13 Preparation of 1R )-2-oxo-N-sulfanilyl-3-endobornanecarboxamide v sodium 40 g. of (lR)-N-(N-acetylsulfanilyl)-2-oxo-3- endobornanecarboxamide sodium are heated to reflux with 500 ml, of ethanolic hydrochloric acid for 1.5

hours. After filtration. the reaction solution is concentrated under vacuum and the residue is taken up in ethyl acetate and water. Work up of the organic phase carbamoylphenyl)-sulfonyl]-2-oxo 3-bornanecarboxamide as a mixture of the endo and exo isomers. The sodium salt crystallizes with 1 mol. of ethanol and 1 mol. of water and melts at 21 8 220 (from ethanol/water).

EXAMPLE Preparation of lR) N-[ {p-]2-(5-chloro-o-anisamideo)-ethyl]-phenyl} -sulfonyl]-2-oxo-3 -endobornanecarboxamide In an analogous manner to Example 1. from D-camphor-3-carboxylic acid chloride and 4-[B-(2- methoxy-S-chloro-benzamido)-ethyl]- benzenesulfonamide there is obtained {p-[ 2-( 5-chloro-o-anisamido )ethyl ]-phenyl} -sulfonyl] crystallized with 1 mol. of ethanol and 0.5 mol. of water, melts at l08l 10 (from ethanol).

yields 26.3 g. of an oily substance which is dissolved in v 300 ml. of absolute ethanol and treated with 3 g. of sodium hydroxid e dissolved in 6 ml. of water. The resulting solution is thereafter concentrated under vacuum and the residue twice distilled with absolute ethanol, whereby there is obtained (lR)-2-oxo-N-sulfanilyl-3- endobornanecarboxamide sodium, which crystallized with 0.8 mol. of ethanol and 0.2 mol. of water, melts at EXAMPLE 14 Preparation of l R )-N-[ (p-carbamolphenyl)-sulfonyl]-2-oxo-3-bornanecarboxamide sodium In an analogous manner to Example 1, from D-camphorJ-carboxylic acid chloride and 4-sulfamoly-benzoic acid amide there is obtained (lR )-N-[(p- EXAMPLE 16 Preparation of I lR)-N-[ (p-cyanophenyl)-sulfonyl]-2-oxo-3-endobornanecarboxamide In an analogous manner in Examplel, from D-camphor-3-carboxylic acid chloride and pcyanobenzenesulfamide there is obtained (lR)-N-[(pcyanophenyl)-sulfonyl]-2-oxo-3-endobornanecarboxamide having a melting point of l63l66 (from ethanol/water); [01],, 324 (in ethyl acetate).

EXAMPLE 17 Preparation of endoand exo-isomers of lR)-N-[ (p-carbamoylphenyl)-sulfonyl]-2-oxo-3-bornanecarboxamide 10 g. of( lR)-N-[(p-cyanophenyl)-sulfonyl]-2-oxo-3- endobornanecarboxamide are dissolved in 350 ml. of

acetone. The solution is treated with ISO ml. of hydrogen peroxide, brought to a pH of l0.5 l by the addition of concentrated sodium hydroxide solution and heated for 5 or 6 hours at reflux so that the pH of the reaction mixture, through the addition of sodium hydroxide, is' maintained constant. Thereafter, the reac- EXAMPLE 18 Tablets of the following composition are prepared, utilizing conventional procedures:

' endobornanecarboxamide 200 mg Gelatine 6 mg Corn starch 88 mg Talc 5 mg Magnesium stearate 1 m We claim: 1. A compound of the formula -2-oxo-3-endobornanecarboxamide which 3 ,8 2 1 ,230 9 10' R or salts thereof with pharmaceutically acceptable basel R 2. A compound 1n accordance with claim 1, wherein Er R is methyl.

K ONHS 5 3. A compound in accordance with claim 2, wherein l R and R taken together, are oxygen.

4. A compound in accordance with claim 2, wherein R is hydrogen and R is hydroxy.

wherein the residues R are identical and are hydro- 5. A compound in accordance with claim 2, (lR)-2- gen or methyl, R is hydrogen, R is hydroxy. or R m oxo-N-(piperidinosulfonyl)-3-endobornanecarboxaand R taken together, are the oxygen atom of a mide. keto group, and R is piperidinyl or pyrrolidinyl,

- UNITED STATES PATENT sewer QETEMQATE @F RRETWN Patent No. 3,321,230 Dated June 28, 1974 Inventofls) Hermann Bretschneider et a1.

It is certified that error appears in the above-identified paterit and that said Letters Patent are hereby corrected as shown below: 7

Cover page, after [21]"App1. N0.: 296,481 insert [:30] Foreign Application Priority Data February 14, 1969 Switzerland 2257/69 June 12 1969 Switzerland 8969/69 Signed and sealed this 11th day of March 1.975,

(SEAL) Attest:

C, MARSHALL DANN RUTH Cr, MASON Cenmissioner 0f Patents Attesting Officer and Trademarks 

2. A compound in accordance with claim 1, wherein R is methyl.
 3. A compound in accordance with claim 2, wherein R1 and R2, taken together, are oxygen.
 4. A compound in accordance with claim 2, wherein R1 is hydrogen and R2 is hydroxy.
 5. A compound in accordance with claim 2, (1R)-2-oxo-N-(piperidinosulfonyl)-3-endobornanecarboxamide. 